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20

Aug

2014

Digging Into the Biochemistry of Lizard Tail Regeneration

Many lower species are far more proficient at regeneration than mammals. Some tiny creatures like hydra are enormously capable regenerators, and may even be so good at it that they are effectively ageless. But the simple strategy of "regenerate and replace everything, all the time" is most likely inapplicable to higher organisms that need to maintain the complex fine structure of the brain and central nervous system: a sweeping regeneration of much of the brain would most likely be equivalent to death for mammals, erasing the data of the mind and disrupting other structures and relationships necessary for moment to moment survival.

The ability of species such as salamanders, zebrafish, and lizards to regenerate inner organs, tails, fins, and limbs is much more interesting however. These animals have complex central nervous systems, yet can rebuild portions of themselves and recover from injuries that would permanently cripple or kill most mammals. A fair amount of research in recent years has focused on salamander regeneration, but at this point it is still too early to say whether it will be practical to take any of what is learned and produce a way for mammals to regenerate in the same way. Perhaps the necessary biochemical tools lie buried in the mammalian metabolism, turned off at some point in the deep evolutionary past, or perhaps they have been lost entirely.

It is clearly the case, based upon the fortuitous discovery of MRL mice capable of healing small wounds without scarring, that there are potential improvements to be made. But it is unlikely that there is much shared biochemistry to be found in the mechanisms involved in regeneration in MRL mice, salamanders, and zebrafish. Biology is complex and it is often the case that any two species found to have evolved similar capabilities actually use completely different mechanisms under the hood.

So to the green anole lizard, which like the salamander is capable of tail regeneration. As it turns out, the way in which that regeneration happens is very different in these two species. This somewhat strengthens the case for tempering any optimism regarding limb and organ regeneration in humans achieved via this means. If researchers are in fact examining a range of independently evolved mechanisms in these various species, it renders it less likely that there is a shared heritage dormant in mammals, and more likely that it will be very hard to recreate these forms of regeneration in humans - no shortcuts here. But again, it really is far too early to have more than suspicions about where this will all go. This group of researchers seem optimistic about the study of lizard regeneration, however:

"Lizards basically share the same toolbox of genes as humans. Lizards are the most closely-related animals to humans that can regenerate entire appendages. We discovered that they turn on at least 326 genes in specific regions of the regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing. Regeneration is not an instant process. In fact, it takes lizards more than 60 days to regenerate a functional tail. Lizards form a complex regenerating structure with cells growing into tissues at a number of sites along the tail."

Other animals, such as salamanders, frog tadpoles and fish, can also regenerate their tails, with growth mostly at the tip. During tail regeneration, they all turn on genes in what is called the 'Wnt pathway' - a process that is required to control stem cells in many organs, such as the brain, hair follicles and blood vessels. However, lizards have a unique pattern of tissue growth that is distributed throughout the tail.

"We have identified one type of cell that is important for tissue regeneration. Just like in mice and humans, lizards have satellite cells that can grow and develop into skeletal muscle and other tissues. Using next-generation technologies to sequence all the genes expressed during regeneration, we have unlocked the mystery of what genes are needed to regrow the lizard tail. By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."

We have carried out the first transcriptomic analysis of tail regeneration in a lizard, the green anole Anolis carolinensis, which revealed 326 differentially expressed genes activating multiple developmental and repair mechanisms. Specifically, genes involved in wound response, hormonal regulation, musculoskeletal development, and the Wnt and MAPK/FGF pathways were differentially expressed along the regenerating tail axis.

However, high levels of progenitor/stem cell markers were not observed in any region of the regenerating tail. Furthermore, we observed multiple tissue-type specific clusters of proliferating cells along the regenerating tail, not localized to the tail tip. These findings predict a different mechanism of regeneration in the lizard than the blastema model described in the salamander and the zebrafish. Thus, lizard tail regrowth involves the activation of conserved developmental and wound response pathways, which are potential targets for regenerative medical therapies.

Comments

Well the good thing, regarding the discovery that there are vastly different mechanisms of regeneration within species, is that it also means we can always find alternative ways to regenerate limbs in humans.

If other animals came up with different methods, then maybe we can engineer one for ourselves (probably by taking inspiration here and there).

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